Project Summary/Abstract - Overall: This highly innovative research program will investigate the use of pharmacologic ascorbate (P-AscH-. high- dose, IV delivery of vitamin C) in the treatment of cancer. Intravenous ascorbate, but not oral ascorbate, produces high plasma concentrations (15-20 mM), which are in the range that are selectively cytotoxic to cancer cells. Studies from our highly integrated translational research team have demonstrated that P-AscH- selectively induces oxidative stress and cytotoxicity as well as radio-chemo-sensitization in pancreas, lung, and brain cancer vs. normal cells. In parallel ongoing pancreas, brain, and lung cancer clinical trials within our program P-AscH- has been shown to be safe and well-tolerated when combined with standard of care radio- chemo-therapies. We have firmly established in all our model systems that P-AscH- is a pro-drug for delivery of hydrogen peroxide (H2O2). These results have led to the overarching hypothesis that aberrant cancer cell oxidative metabolism dysregulates labile redox active metal ion pools enhancing P-AscH- oxidation to form H2O2. The overall theme of this Program Project application is that P-AscH- can be used as an easily implementable clinical adjuvant to conventional radio-chemo-therapies that will selectively target cancer vs. normal cells by increasing H2O2 formation. Furthermore, this mechanism appears to be broadly applicable to several cancers. The current application applies these principles to highly integrated approaches, mechanisms, and biomarkers in the use of P-AscH- as an adjuvant in to the treatment of pancreatic ductal adenocarcinoma (PDAC, Project 1), non-small cell lung cancer (NSCLC, Project 2), and glioblastoma multiforme (GBM, Project 3). The Administrative Core (Core A) will coordinate all aspects of the project and bio-statistical analysis. The Biomarkers Core (Core B) will interact with all three projects by providing confirmation of P-AscH- dosing in all clinical trial subjects and in preclinical models as well as supporting the measurement and molecular manipulation of markers of oxidative stress, redox active metals, and antioxidant enzymes in vitro and in vivo. The Clinical Trails Core (Core C) will coordinate all the efforts in the clinical trials including accrual of subjects, data management, regulatory oversight, and reporting. Successful completion of this proposed program project will demonstrate the feasibility of an easily implemented new paradigm in complementary approaches to redox metabolism-based cancer therapy utilizing P-AscH- that could provide the foundation for large scale phase 3 multi-institutional cooperative group trials. Since the approach is based on targeting fundamental differences in the redox biochemistry/metabolism of P-AscH- in cancer vs. normal tissues, these studies also have the potential to demonstrate if functional imaging and redox sensitive biomarkers can provide a robust platform for predicting therapeutic responses to P-AscH-.